The injury of central nervous system tissues causes various types of diseases. For example, cerebral infarction is caused by the necrosis of brain tissues due to ischemia. Parkinson's disease is a neurodegenerative disease caused by degeneration of dopamine-producing cells existing in the substantia nigra in the midbrain. Spinal cord injury is mainly caused by damaging the spinal cord by strong external force.
The disorders of motor function, sensory function and cognitive function are generated as a result of the loss of central nervous system tissues. It is known that the central nervous system tissues have an extremely poor regenerative power. Thus, if these tissues are once injured, it is basically difficult to treat them. At present, rehabilitation and the like are undergone to recover lost function. However, it takes a long period of time to obtain the effects of such rehabilitation, and further, the recovery of disordered function is extremely difficult.
However, in recent years, the regeneration of the injured central nervous system tissues is attempted by transplantation of foreign cells (which are cells capable of differentiating into nervous cells, such as bone marrow stem cells, neural stem cells, ES cells, and adipose tissue-derived stein cells) (Nat Med 10: S42-S50, 2004).
U.S. Pat. No. 7,682,825 discloses a method of differentiating bone marrow stromal cells to neuronal precursor cells by introduction of notch gene. The inventors investigated stimulation of bone marrow stromal cells by introduction of genes which play a central role in the initial stages of morphogenesis of bone marrow stromal cells, and examined the effects of such stimulation on induction of bone marrow stromal cell differentiation. Specifically, it was expected to be potentially possible to “reset” bone marrow stromal cells by introduction of Notch genes and Notch signaling genes, which play important roles in developmental differentiation of the nervous system and perform functions in determining cell fates when precursor cells branch to neural cells or glial cells. It is important to note that despite implication of Notch genes and Notch signaling related genes in the mechanism of suppressing induction of cell differentiation, it was a completely unexpected finding that combining introduction of Notch genes and Notch signaling related genes with other stimulation to induce differentiation, can also induce differentiation of the very cells into which the Notch genes and Notch signaling related genes have been introduced (not the cells contacting with the cells into which the Notch genes and Notch signaling related genes have been introduced). It cannot be affirmed that introduction of the Notch genes and Notch signaling related genes in the differentiation inducing method of the present invention resulted in resetting of developmental differentiation of bone marrow stromal cells. However, by combination of this gene introduction with other differentiation inducing steps according to the invention, it was possible as a result to provide a method of efficiently inducing differentiation of bone marrow stromal cells to neural cells or skeletal muscle cells.
US2006/0216276 discloses a method of administering neuronal precursor cells transdifferentiated from marrow adherent stem cells by introduction of Notch intracellular domain gene to patients with injured central nervous system tissues, and particularly to patients with cerebral infarction. However, this method is problematic in that the cells flow out after transplantation, and also in that the survival rate of the transplanted cells is low. Among the transplanted cells, only a very small number of cells may survive as central nervous system tissues.